Summary Chromosomal translocations are key drivers of oncogenic transformation and frequently determine the biology and response to therapy of cancer cells. The mechanisms that generate the DNA double strand breaks (DSBs) that initiate chromosomal translocations are well known in hematologic cancers but poorly understood in solid tumors. In lymphoma and leukemia, most DSBs that lead to an oncogenic translocation are generated by the activity of enzymes such as RAG1/2 and AID. These enzymes are physiologically responsible for the rearrangements of the immunoglobulin genes, but can initiate a translocation when they aberrantly target other genes. In contrast, in solid tumors where RAG1/2 and AID are largely not expressed, it is unclear what factors initiate DSB formation. Physical factors, such as UV light or irradiation, or factors intrinsic to the DNA structure or replication are thought to be responsible for part of the DSB and translocation formation, but they are insufficient to explain the recurrent patterns of oncogenic translocations in solid tumors. Recently, the APOBEC proteins have been linked to peculiar mutational signatures found in several solid cancers, including lung and breast cancers. Importantly, the APOBEC-dependent mutational signatures typically co-localize with genomic rearrangements such as translocations and somatic copy number alterations (SCNAs). Based on these correlative findings and preliminary experiments, our hypothesis is that APOBEC enzymes could be responsible not only for somatic mutations but also for the formation of chromosomal translocation in solid tumors. We will test this hypothesis by applying innovative sequencing techniques we developed in our lab to identify and map recurrent translocations induced by APOBEC proteins in different cell types. We will apply these techniques both in in vitro assays as well as to in vivo models of translocation formation. The demonstration that APOBEC protein can initiate translocation formation has the potential to provide a key mechanistic link that is currently missing to explain recurrent structural aberrations in cancer. From this demonstration, a variety of new research lines will open including potential therapeutic applications aimed at blocking APOBEC activity to reduce genomic instability in cancer.